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Good Manufacturing Practice (GMP) regulations were introduced as a

means to ensure that a given product is processed reliably, repeatedly,
consistently, safely and to a high quality. In the pharmaceutical processing
industry GMP is an essential part of the production process. Centrifuges
are a major processing tool used in this industry. In the following article,
Nigel Day discusses the implications that GMP has had on the design,
manufacture and operation of industrial centrifuges, with a particular focus
on horizontal peeler type machines.

GMP in pharmaceutical processing

and its implications for centrifuges
Summary of GMP principles

J
ust prior to the start of the 2nd World War there was a
serious poisoning incident in the USA. This prompted the
introduction of the “Food, Drugs and Cosmetics Act 1938”,
produced by the US Food and Drugs Administration (FDA). The
intention of the new act was to ensure that food, drugs, cosmetics
and biological products were safe for human contact. Hence the
need to establish the Good Manufacturing Practice (GMP).
GMP regulations specific to the production of drugs and active
pharmaceutical ingredients (API's) are covered by the FDA
regulation 21CFR parts 210 & 211. Internationally, it has also
been adopted and is currently covered by the European Union (EU)
directive 356.
GMP regulations incorporate the keeping of records,
individual's qualifications, cleanliness, sanitation, equipment
verification, validation and procedural reviews.
While appearing at times rather rigid most GMP requirements
are “open ended”, allowing individual manufacturers flexibility to
decide for themselves how best to meet the necessary controls.
GMP is often referred to as cGMP, with the “c” indicating that
the latest or “current” technologies and systems are required or
being adopted. This simple prefix is important as it prevents errors
or misunderstanding. For instance GMP requirements of one or
two decades ago are almost certainly not acceptable by today's far
higher standards.
Image courtesy of Rousselet-Robatel UK
The international Society of Pharmaceutical Engineers (ISPE) has
succinctly summarized the under lying principles of GMP with a
set of ten rules.
• Compile detailed written procedures
• Follow these procedures
• Document (record) the work
• Validate the systems and processes
• Design and build proper facilities and equipment
• Maintain the facilities and equipment
• Must be competent
• Maintain cleanliness
• Control of quality
• Audit regularly for compliance
Implications for industrial centrifuges
Having established the general principles surrounding GMP we
now take a closer look at the implications they impart with
specific thought to the horizontal basket filtration peeler type
centrifuge.
Processing equipment such as an industrial centrifuge must be
manufactured so it can successfully process a given product
reliably, repeatedly, consistently, safely and to a high quality. All of
which must be capable of validation.

GMP guidelines for an industrial centrifuge, especially those

employed in the pharmaceutical processing industry, must ensure
the following:
1. The equipment must not allow the product in question to
become contaminated while being processed.
2. All contact surfaces must not allow products to become
impregnated into its structure. They should also be of suitable
specification, so as to prevent any chemical reaction.
Lubrication products must be contained and prevented from
coming into contact with the product.
3. Where ever possible the primary separation vessel should be
fully enclosed for as long as possible, so as to prevent
contamination of the product by the outside environment, as
well as avoiding the product falling into contact with
operators.
4. There needs to be provision to maintain product integrity

20 March 2004 ISSN 0015-1882/04 © 2004 Elsevier Ltd. All rights reserved

from batch to batch. This means the design needs to prevent
the build up of product, microorganisms, pathogens, etc. To
achieve this there needs to be acceptable provision to clean
and/or sanitize the product contact areas. Residual product
remaining on the filter media may also require removal
periodically. Specific removal devices must, therefore, be
incorporated.
5. The centrifuge must be operated, maintained, cleaned and
inspected by adhering strictly to detailed written procedures.
As indicated earlier GMP requirements are very much open to
the individual's interpretation. Therefore it has fallen upon the
centrifuge design engineers to generate far more specific guidelines
and procedures for their own organization to follow.
A common starting point, adopted by several leading centrifuge
manufacturers, is to divide the more detailed procedures into
separate categories or zones. For instance there is the “product
zone”. This is where the product shall be processed. For a centrifuge
this will need to cover the basket, feed and wash pipes, cake depth
indicator mechanism, solids discharge mechanism (plough), the
solid/liquid discharge arrangements and not forgetting the outer
casing that encapsulates them all.
Contrary to the product zone there is also the
“non-product zone”. This takes into account components such as
drive motors and transmission belts.
There is also a third zone, which can be easily neglected. Some
manufacturers refer to this as the “splash zone”. This zone is
where product, following maintenance or inspection, comes into
contact with such areas as the exterior of the centrifuge and
equipment located on it.
Product zone
In order to prevent the accumulation of product, which could
promote the development of bacteria or other microorganisms,
the centrifuge engineer must pay particular attention to the
following. This list is by no means exhaustive but does cover the
most common aspects:
1. All surfaces need to be readily cleaned and not cause possible
contamination or chemical reaction with the product being
processed. The material of construction will have been
decided upon prior to manufacture following consultation
with the client. Any angles or tight corners must be rounded
to create a smooth radius. If at all possible there should be no
shelves, ledges or other projections that could hold up
products within the processing area.
2. Product delivery and filtrate take-off arrangements must be
free draining with no hang up areas. Solids discharge chutes
or hoppers must have sufficient angle to be self-cleaning.
Flowability properties of the final solid phase is frequently
neglected.
3. Welded joints must be continuous [ i.e. no stitch welding] and
their fillets fully ground smooth to a minimum of
approximately 3mm. Butt welds need to be ground and
smoothed flush.
4. No permanent joints should be designed in such a manner
that they minimize the level of product that can become held
up or collected in recesses or crevices. Employment of
threaded fasteners in the product zone must be avoided,
unless it’s practically impossible to do so.
5. Use of conventional bearings, lubricated with oils and grease,
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Image courtesy of Thomas Broadbent & Sons Ltd
cannot be located in the product zone. Dry bushings or
product lubricated, such as PTFE, can be permitted, but must
be fully considered before their incorporation.
6. Pipework and associated fittings should have been
manufactured to a recognised standard such as BS4825 or
DIN standard equivalent.
Given all the consideration above it is imperative that
provisions are made to accommodate an automated cleansing
system. Commonly referred to, as “cleaning in place” or “CIP”,
such a system will ensure the product zone is thoroughly cleaned.
This drastically reduces the need to open the processing “vessel”.
Certain products call for enhanced cleaning requirements. Here
we may well find a “sanitize or steam in place” system (SIP) in
addition to the CIP arrangement. The installation of either a CIP
and/or SIP system requires them to be reliable, repeatable and
most importantly, validatable.
Entry to the centrifuge at some stage will be necessary, if only
to replace the filter media. However, the particular tasks required
must have the simplest of procedures in order to minimize
operator contact with the product zone, and the product zone with
the environment.
Non-product zone
Requirement for the non-product zone are considerably less
stringent. All exposed surfaces must be corrosion/erosion resistant
or adequately treated with a protective coating.
Their overall construction must be such that it avoids retention
of moisture or lubricants, while at the same time facilitating
inspection, servicing and cleaning.
Splash zone
Areas of concern here are vary similar to those highlighted for the
product zone. Having said that they are in general much less
stringent. Material specification, surface finishes, corners, angles,
and so on, can normally be of a reduced quality. Lubricated
bearings are now acceptable, as long as their lubricants are
compatible with the product to be processed.
Cleaning the centrifuge will be carried out manually so
there is no requirement for complex cleaning systems, such
as CIP or SIP.
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Validation
A key aspect of GMP is the validation process. Validation is
documentary evidence that provides a high level of assurance that
a specific process will consistently produce a product that satisfies
predetermined specification and quality.
Validation procedures are rather detailed and difficult to fully
explain in such a relatively short article as this. On the other hand
how they interact with each other throughout the design, manu-
facture, installation and operation of the centrifuge is quite logical.
The figures below attempt to show how all stages of the
validation process interact. The validation process can be
conveniently broken down into three main categories:
• Specification
• Qualification
• Acceptance
(i) Specification
• URS (User Requirement Specification) - what the centrifuge is
expected to do. Produced by the client.
• FS (Functional Specification) - what the functions of the
centrifuge are and how they will comply with the URS.
• DS (Design Specification) - details how the FS and the URS
requirements will be achieved. This normally includes
mechanical, electrical and software specifications.
• Audit Supplier - the end user audits a supplier to ensure a
quality management system is in operation that appreciates
the importance of GMP.
• Planning - once a supplier is highlighted a comprehensive plan
of action is produced. Essentially there will be an overall
“project plan”, as well as a “quality plan” and a “validation
plan”. Such planning will determine responsibilities,
milestones and other time scales.
(ii) Qualification & acceptance
• DQ (Design Qualification) - verifies that the supplier has
designed the centrifuge in accordance with an appropriate
quality management system such as ISO9000.
• IQ (Installation Qualification) - verifies the centrifuge
complies with current codes of practice and regulation and is
in accordance with the requirements of the client.
22 March 2004
• OP (Operational Qualification) - confirms the centrifuge
operates fully as designed. It also confirms the requirements
of the Functional Specification.
• PQ (Performance Qualification) - this confirms the centrifuge
performs as intended. This also confirms that the URS has
been successfully achieved.
Collectively the above provides documentary conformation
that the centrifuge is fit for its purpose and capable of repeatedly
producing the desired level of product quality.
At each stage of the qualification there is a series of “acceptance
tests” to be undertaken before moving onto the next stage.
• DAT (Development Acceptance Tests) - client accepts the
development and planning phases of the project.
• FAT (Factory Acceptance Tests) - prior to leaving the
manufacturer’s premises the completed centrifuge is tested.
The testing follows written procedures covering the function
and operation of the centrifuge.
• SAT (Site Acceptance Tests) - once installed on the client’s
premises the centrifuge undergoes another series of tests,
again following detailed written procedures. It is at this point
of the project that the centrifuge must demonstrate it is
capable of processing the product in question, repeatedly and
within the specified quality limits. Normally this test is
judged following the processing of three consecutive batches.
Once all the above validation is completed a final document –
the Validation Report – is required to successfully hand over the
centrifuge to the care of the client.
Horizontal peeler type centrifuges
The horizontal peeler centrifuge has been around far longer than
most people realize. Records show that machines that are almost 75
years old are still in operation. However, they are a long way removed
from designs and specifications of today's pharmaceutical industry.
Originally they were specifically designed to fully process a
product at a single speed, thus challenging the performance of the
more conventional vertical batch basket centrifuge configuration,
which had a considerable amount of “dead” time as it accelerated
and decelerated between differing processing speeds.
While this is still the case to some extent, many more benefits
can now be realized with the horizontal axis designs, especially
when closely following GMP requirements.
From the images kindly provided by leading manufacturers to
accompany this article, it can be seen how the following of cGMP
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requirements has resulted in the configuration/design of the
centrifuge becoming almost identical.
One common feature adopted by most of the manufacturers is
to incorporate a “through the wall design”. Essentially this is
where the centrifuge layout is divided into two, forming a “clean
end” and a “dirty end”. This is achieved by a large plate that goes
around the centre of the centrifuge. The centrifuge is then pushed
through an opening in the wall up to the plate and sealed in place

Image courtesy of Comi Condor UK

via a flexible membrane.
Compliance with GMP requirements in the pharmaceutical
processing industry, especially when considering centrifuges, has
resulted in virtually all new installations being of the horizontal
axis type. The days of the vertical axis batch filtration centrifuges
in today’s GMP orientated pharmaceutical processing sector are
sadly numbered. On the other hand for those offering horizontal
axis units, and continually developing their designs, the future
appears very promising.

Acknowledgement
The author would like to thank Thomas Broadbent & Sons Ltd,
Rousselet-Robatel UK and Comi Condor UK for their assistance
with the article and the supply of photographs.

Contact:
Nigel Day, NCD Separation Solutions Ltd,
4 Healey View, Issett, Wakefield WF5 8LX, UK.
Tel/Fax: +44 1924 270 369;
E-mail: info@ncdsep-solutions.co.uk;
Website: www.ncdsep-solutions.co.uk

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